Synthesis, Characterization, and Molecular Docking Studies of Novel Picolinohydrazide Derivatives as Potential Antibacterial Agents Targeting 1AJ0 Protein

Abstract

Bacterial resistance is one of the most immediate problems in healthcare and it requires coordinated efforts for the designing of novel antimicrobial strategies. The current study, represents the design and simulation analysis of four novel heterocyclic compounds (4, 7) derived from a sequential three, step methodology. The methodology included acid, catalyzed esterification of picoline, followed by hydrazide formation, and anhydride coupling reactions to obtain the target compounds with the yield ranging from 50% to 60%. The target molecules (4, 7) were structurally specific, as confirmed by ATR, FTIR, 1H, NMR, and 13C, NMR spectroscopic methods. MOE software was used for the simulation of the target molecules to evaluate their binding affinities with 1AJ0 target bacterial proteins, which are the decisive components of metabolic pathways in prokaryotes. The molecules tested exhibited greater binding affinities, as in the case of compound 7 with, -5.88 Kcal/mol binding affinity, showing a remarkable enhancement of about 31. 5% compared to the control, -4.47 Kcal/mol. This outstanding improvement could be interpreted by the optimal H-bonding with residual ARG A:255, LYS A:221, HIS A:257 and THR A:62, complementary by π- system interactions that reinforce molecular complex stability. Our findings suggest that the synthesized compounds could serve as valuable lead compounds for developing the next generation antimicrobial agents with improved activity and optimized pharmacokinetic characteristics.